Tumor suppressor
Tumor suppressors are a large group of normal proteins, that are capable of controlling cell division, promoting apoptosis, detecting and repairing DNA mistakes, differentiation and migration and suppressing metastasis. In contrast to oncogenes, tumour suppressor genes are genes that would normally prevent a tumour from happening and that need to be inactivated for a tumour to start to form. Therefore tumor suppressors are from times to times also called anti-oncogenes. Mutations of tumour suppressors are present in somatic, but also in germ cell lines. Two-hit hypothesis The cancer preventing effects of tumour suppressors usually require the presence of at least one functional gene. Therefore both copies of a tumour suppressor gene have to be inactivated. Prototypic tumor suppressor genes are therefore recessive and reguire "two-hit" inactivation of both alleles. Alfred Knudson (1971) proposed this two-hit model of tumor suppressor inactivation. Knudson deduced that in case gene inactivation is a random process, people who inherit an inactivated copy of a tumor suppressor gene have a higher risk of developing associated forms of cancer than people born with two normal copies. It was shown that in tumors in these predisposed patients, the remaining wild-type copy of the tour suppressr gene was lost. The process of losing the last functional allele is referred to as loss heterozygosity (LOH). Li Fraumeni syndrome Is a rare autosomal dominant disease (dominant at the level of the whole organism, but recessive on the cellular level) associated with the mutation of the tumor suppressor gene p53 (17p13). It is associated with a frequent occurece of malignities of various kinds such as: sarcomas, breast cancer, brain tumour, leukemia,... Retinoblastom Is a rare, but well known disease. It is a typical example of hereditary disposition of tumors. Knudson's two-hit hypothesis theory was proposed based on the epidemiologic studies of retinoblastoma. It is associated with mutations in the Rb protein. Rb mutations are recessive on the cellular level, but dominant on the level of the whole organism. A hereditary mutation in Rb (13q14) predisposes the individual towards generation of retinoblastoma (a malignant tumor of retina) in a low age. In addition to this, barers of the RB mutation are also predisposed towards osteosarcomas. Examples of tumour suppressors *p53 *Rb (retinoblastoma protein) *APC (adenomatosis polyposis coli) *PTEN (phosphatase tensin homolog) *MSH2 (mutS homolog 2) *ATM (Ataxia-telangiectasia) *BRCA (breast cancer protein) Functions Suppression of cell division Suppression of cell division is the main mechanism for most tumor suppressors (i.e. Rb, p53 and APC). Rb protein inhibits transcription of specific genes, which are required for mitosis through binding to transcription factors such as E2Fs. E2Fs are key regulators of cell proliferation. p53 functions as a transcription factor and stimulates expression of other genes, such as WAF1/CIP1 encoding p21. APC stabilizes microtubules to inhibit mitosis and interferes with cell adhesion to its growing matrix. Induction of apoptosis Apoptosis, or programmed cell death, is another functional mechanism of tumor suppression. Examples of this group of tumor suppressors are p53, APC, cluster of differentiation 95 (CD95), bridging integrator 1 (Bin1) and phosphatase and tensin homolog (PTEN). DNA damage repair The tumor suppressors that can help in DNA damage repair include mutS homolog 2 (MSH2), mutL homolog 1 (MLH1), Ataxia-telangiectasia-mutated gene product (ATM), breast cancer protein (BRCA), Nijmegen breakage syndrome 1 (NBS1), Fanconi-Anemia−related tumor suppressor (FA), and p53. Inhibition of metastasis Some tumour suppressor proteins are involved in cell adhesion- prevent tumor cells from dispersing, blocking loss of contact inhibition and inhibition of metastasis. These proteins are known as metastasis suppressor. Tumor suppressors that can inhibit metastasis consist of metastin, breast cancer metastasis suppressor 1 (BRMS1), tissue inhibitor of metalloproteinase (TIMP), cofactor required for specificity protein 1 activation (CRSP), and KAL1/CD82. References Sun W. and Yang J., Functional Mechanisms of Human Tumor Suppressors , Journal of Cancer, 1:'136-140 (2010) Hohensten P., 'Tumor Suppressor Genes- One Hit Can Be Enough , '''PLoS Biol '''2: e40 (2004) Sherr Ch.J, Principles of Tumor Suppression , '''Cell, '''116: 235-246 (2004)